Interleukin-6 Receptor Antibody Research Articles

IL-6 receptor antibody treatment improves muscle weakness in experimental autoimmune myasthenia gravis mouse model.

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness and fatigue. It is caused by pathological autoantibodies against components expressed at neuromuscular junctions, such as acetylcholine receptor (AChR). Interleukin-6 (IL-6) has been suggested to play a role in the pathogenesis of MG, and IL-6 receptor (IL-6R) antibody treatment may provide a novel therapeutic option. In this study, we investigated the effects of IL-6R antibody treatment in an experimental autoimmune MG (EAMG) mouse model. We demonstrated that IL-6R antibody treatment improved muscle weakness, reduced IgG deposition at neuromuscular junctions, and the levels of AChR autoantibodies in serum. In addition, follicular helper T cells and Th17, plasma cells in lymph nodes were lower in IL-6R antibody treated mice. Our findings suggest that IL-6R blockade may be a novel and effective therapeutic strategy for the treatment of MG.

CNSC-26. GLIOBLASTOMA-NEURONAL CIRCUIT INTEGRATION IS MODULATED BY INTERLEUKIN-6

Abstract The pleiotropic cytokine interleukin-6 (IL-6) is known to be involved in both pro- and anti-inflammatory signaling cascades. In glioblastoma studies using animal and human models, IL-6 promotes immunosuppression and tumor progression and is negatively associated with survival. Intriguingly, IL-6 also contributes to increased synaptogenesis during development and following focal brain injury. Glioblastoma remodeling of neuronal circuits influences patient survival; therefore, it is possible that IL-6 has mechanistic significance. Here, we investigated IL-6 as a driver of activity-dependent glioblastoma proliferation using patient-derived xenograft (PDX) mouse and human glioblastoma models. We assessed neuronal activity by microelectrode arrays and in vitro calcium imaging using weighted mean firing rate (WMFR), network burst frequency (NBF), and synchrony index. Next, we used bulk and single-cell RNA sequencing on 13,731 cells from ten tumors including pair-matched samples to identify differentially expressed genes in intratumoral regions with elevated functional connectivity and found IL6 to be highly upregulated. Mouse embryonic cortical neurons and cerebral organoids co-cultured with primary patient-derived glioblastoma cells demonstrated concentration-dependent neuronal hyperexcitability (increased WMFR and NBF) in IL-6-overexpressing conditions compared to the neuron-only condition. Pharmacological inhibition using the humanized IL-6 receptor antibody tocilizumab reduced network synchrony across models. These findings suggest that IL-6-induced glioma-neuronal hyperexcitability may be inhibited by the FDA-approved tocilizumab, thereby providing preclinical support for its use to treat activity-dependent mechanisms of glioblastoma proliferation. Future studies are needed to uncover mechanisms and clinical efficacy.

Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.

Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.

Development of a New Method to Evaluate the Biodistribution of Antibodies Using Non-Radioactive Metal Labeling and Inductively Coupled Plasma Mass Spectrometry.

The use of radiolabeled compounds is associated with a number of limitations. Therefore, a new method for the radioisotope-free evaluation of antibody distribution using metal labeling and inductively coupled plasma-mass spectrometry (ICP-MS) was developed herein. Indium-labeled monoclonal antibodies were administrated intravenously to tumor-bearing mice and cynomolgus monkeys, and antibody concentrations in plasma and tissues were measured by ICP-MS. The results were compared with those obtained using a ligand binding assay (LBA) and radioisotope-labeled antibody administration. Indium-, terbium-, holmium-, and yttrium-labeled cetuximab were co-administered to one C57BL/6J mouse for simultaneous PK and tissue distribution evaluations. The administration of a radioactive or non-radioactive indium-labeled anti-human interleukin-6 receptor (hIL-6R) antibody to tumor-bearing hIL-6R transgenic mice resulted in similar plasma antibody concentration-time profiles by ICP-MS, a ligand binding assay (LBA), and gamma-ray detector. Liver, kidney, brain, spleen, and tumor concentrations of antibodies measured by ICP-MS were similar to those after the administration of radiolabeled anti-hIL-6R antibodies. Following the administration of indium-labeled cetuximab to cynomolgus monkeys, plasma antibody concentrations measured by ICP-MS were similar to those measured by LBA, and antibody concentrations in organs were evaluable by ICP-MS. The PK of all metals were similar to antibody PK evaluated by LBA, and concentrations in each tissue were equivalent among metals. The assessment of antibody distribution using ICP-MS is a novel alternative to the traditional radiolabeled approach. It facilitates the assessment of antibody distribution in the early stages of drug discovery and accelerates the assessment of target engagement.

Update on Adult-Onset Still's Disease: Diagnosis, Therapy and Guideline

Adult-onset Still's disease (ASOD) is an autoinflammatory disease of unknown etiology which is pathogenetically characterized by an involvement of the innate immune response with activation of neutrophils and an increased secretion of IL-1, IL-6, IL-18, type 1 interferons. Still's disease may occur at any age with distinct variability in signs and symptoms. Recently, the German Society of Rheumatology (DGRh) has issued an AOSD guideline which recommends diagnosing AOSD based on a characteristic combination of symptoms including intermittent fever, rash, arthralgia, and arthritis after exclusion of infections, neoplasms and other rheumatological conditions. Classification criteria according to Yamaguchi may support the clinical diagnosis. Therapy is recommended to include glucocorticosteroids and methotrexate or ciclosporin, at higher activity levels IL1-receptor antagonist anakinra, IL-1β antibody canakinumab, or IL6-receptor antibody tocilizumab. At a high disease activity, anakinra or canakinumab may be employed primarily. Local drug licensing policies may have to be considered, as these substances are not universally approved in these scenarios. Important complications to consider consist in perimyocarditis, a multi-faceted pulmonary involvement, and macrophage activation syndrome (MAS). MAS features multi-organ involvement and cytopenias. Besides supportive measures often requiring intensive care, high dose glucocorticosteroids as well as above named biologics, and if necessary, also etoposide based therapeutic regimen are used.

Tocilizumab, an IL6-receptor antibody, proved effective as adjuvant therapy for cytokine storm induced by severe infection in patients with hematologic malignancy.

Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach.

Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody

BackgroundIndividuals with autism spectrum disorder (ASD) have an increased risk of developing epilepsy. Both ASD and epilepsy have been associated with increased levels of immune factors in the blood, including the proinflammatory cytokine interleukin 6 (IL-6). Mice lacking the synapsin 2 gene (Syn2 KO) exhibit ASD-like behavior and develop epileptic seizures. Their brains display neuroinflammatory changes including elevated IL-6 levels. We aimed to investigate the effect of systemic IL-6 receptor antibody (IL-6R ab) treatment on seizure development and frequency in Syn2 KO mice. Material and methodsWeekly systemic (i.p.) injections of IL-6R ab or saline were given to Syn2 KO mice starting either early in life at 1 month of age, before seizure debut or at 3 months of age, directly after seizure debut and continued for 4 or 2 months, respectively. Seizures were provoked by handling the mice three times per week. The neuroinflammatory response and synaptic protein levels in the brain were determined by ELISA, immunohistochemistry and western blots. In an additional group of Syn2 KO mice, with IL-6R ab treatment early in life, ASD-related behavioral tests including social interaction and repetitive self-grooming, as well as cognitive memory and depressive-/anxiety-like tests, and actigraphy measurements of circadian sleep-awake rhythm were analyzed. ResultsThe IL-6R ab treatment reduced seizure development and frequency in Syn2 KO mice when initiated before, but not after, seizure debut. However, early treatment did not reverse the neuroinflammatory response or the imbalance in synaptic protein levels in the brain previously reported in Syn2 KO mice. The treatment did not affect social interaction, performance in memory, depressive-/anxiety-like tests or the sleep-awake rhythm of Syn2 KO mice. ConclusionThese findings suggest the involvement of IL-6 receptor signaling during epilepsy development in Syn2 KO mice, without significant alterations of the immune reaction in the brain, and independently of cognitive performance, mood and circadian sleep-awake rhythm.

CAR-T Cell Therapy: the Efficacy and Toxicity Balance.

Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy. Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.

Invigorating spleen, replenishing qi and tonifying kidney method treatment of traditional Chinese medicine for myasthenia gravis: A protocol for systematic review and meta-analysis

Myasthenia gravis (MG) is an autoimmune disease related to the production of autoantibodies. It is mediated by antibodies against acetylcholine receptor (AChR), muscle specific kinase (MuSK) or other AChR related proteins in the postsynaptic muscle membrane, which interfere with the transmission of signals at the neuromuscular junction, resulting in clinical symptoms of skeletal muscle weakness and fatigue, leading to the occurrence and development of MG. At present, the incidence rate of Mg is increasing year by year. At present, the method of invigorating spleen, replenishing qi and tonifying kidney in traditional Chinese medicine has been widely used in the clinical treatment of MG, and the effect is good. The purpose of this study was to systematically evaluate the efficacy and safety of the method of invigorating the spleen, supplementing qi and tonifying the kidney in the treatment of MG. We will search from the following eight databases: PubMed, Cochrane Library, EMBASE, Web of Science, CNKI, Sinomed, Wanfang, and Vip. All randomized controlled trial (RCT) literature has been searched and classified since the establishment of the database to date. In this study, two researchers independently screened and evaluated the quality of the retrieved literature. Cochrane risk bias assessment tool was used to evaluate the risk of bias. The meta-analysis uses RevMan 5.3 software provided by Cochrane Collaboration Network for meta analysis. This study compared the main outcome indicators: clinical response rate, recurrence rate, incidence of adverse reactions, quantitative myasthenia gravis score (QMG). Secondary outcomes were clinical absolute score, quality of life score (QOL), levels of inflammatory factors such as IL-6, IL-10, and serum acetylcholine receptor antibody (AChR-Ab) levels. The purpose of this study was to evaluate the efficacy and safety of the method of invigorating the spleen, supplementing qi and tonifying the kidney in treating MG, and to provide evidence based medicine.

Levilimab clinical efficacy for interleukin-6 receptor inhibition in COVID-19 and its potential for treating cytokine release syndrome of other aetiologies

The COVID-19 mortality is associated with an increase in interleukin-6 (IL-6) levels. Levilimab is an anti–IL-6 receptor antibody with proven clinical efficacy in patients with severe COVID-19.The aim of the study was to assess the association of COVID-19 severity and levilimab effectiveness with IL-6 levels and to explore the potential for using levilimab in other conditions accompanied by cytokine release syndrome.Materials and methods: the subgroup analysis was based on the data of COVID patients with known baseline IL-6 levels from the CORONA clinical study. Subgroups were formed according to baseline IL-6 levels: ≤5 pg/mL (normal) and >5 pg/mL (elevated). The subgroup analysis included descriptive statistics of the patients and time courses of their clinical and laboratory findings (at screening, on the day of investigational product administration, and further until day 14). In order to compare the percentages of patients who had required rescue therapy, the authors used Fisher's exact test.Results: the subgroup analysis included 91 patients (47 from the levilimab group and 44 from the placebo group). At baseline, the authors observed elevated levels of IL-6 in 31/47 (66%) subjects in the levilimab group and 29/44 (48.4%) subjects in the placebo group. The subjects with elevated IL-6 demonstrated more pronounced clinical signs of pneumonia and abnormalities in inflammatory markers. Elevated baseline IL-6 levels were associated with the need for rescue therapy (OR=3.714; 95% CI: 1.317–9.747; p=0.0183); this association was stronger in the placebo group (OR=8.889; 95% CI: 2.098–33.31; p=0.0036). Also, the placebo group showed long-term abnormalities in the clinical and laboratory findings.Conclusions: IL-6 is one of the key elements in the pathogenesis of cytokine release syndrome related to COVID-19 and other conditions. Elevated IL-6 levels are associated with the severity of COVID-19. Inhibition of IL-6 receptors by levilimab leads to clinical improvement in patients with severe COVID-19, suggesting the effectiveness of levilimab in pathogenesis-oriented therapy for cytokine release syndrome of other aetiologies.

Limited efficacy of tocilizumab in adult patients with secondary hemophagocytic lymphohistiocytosis: a retrospective cohort study

BackgroundInterleukin (IL)-6 is one of the key cytokines in the pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH); however, the efficacy and safety of tocilizumab (TCZ), a monoclonal IL-6 receptor antibody, in patients with sHLH is uncertain.Methods/ResultsThis study included 64 adult patients who were diagnosed with sHLH based on the HLH-2004 criteria. Patients were classified into two groups based on treatment regimen at baseline: tocilizumab (TCZ group, n = 8) versus other treatments (control group), including HLH-2004 protocol (n = 35), chemotherapy (n = 7), glucocorticoid alone (n = 8), and with other immunosuppressants (n = 6). Primary outcome was overall 8-week survival. Baseline characteristics between the two groups were comparable. At day 56, one patient (12.5%) in the TCZ group and twenty-eight patients (51.9%) in the control group survived. Univariable and multivariable Cox proportional hazard analysis showed that TCZ significantly increased the risk of death (adjusted hazard ratio 5.55; 95% CI 2.13–14.49). The complete or partial response rate at day 14 was 44.6% in the control group, and nil in the TCZ group. In contrast, infectious complications occurred more frequently in the TCZ group than in the control group (14.3% vs. 50.0%).ConclusionOur results suggest that tocilizumab has limited efficacy in treating adult patients with sHLH and could increase the risk of infectious complications compared to the conventional treatments.

Tocilizumab for the Treatment of Familial Mediterranean Fever-A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician’s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.

Effect of Tocilizumab on "Ventilator Free Days" Composite Outcome in SARS-CoV-2 Patients: A Retrospective Competing Risk Analysis.

SARS-CoV-2 infection demonstrates a wide range of severity. More severe cases demonstrate a cytokine storm with elevated serum interleukin-6, hence IL-6 receptor antibody tocilizumab was tried for the management of severe cases. Effect of tocilizumab on ventilator-free days among critically ill SARS-CoV-2 patients. Retrospective propensity score matching study, comparing mechanically ventilated patients who received tocilizumab to a control group. 29 patients in the intervention group were compared to 29 controls. Matched groups were similar. Ventilator-free days were more numerous in the intervention group (SHR 2.7, 95% CI: 1.2 - 6.3; p = 0.02), ICU mortality rate was not different (37.9% versus 62%, p = 0.1), actual ventilator-free periods were significantly longer in tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio of death in tocilizumab group (HR 0.49, 95% CI: 0.25 - 0.97; p = 0.04). There was no difference in positive cultures among groups (55.2% in tocilizumab group versus 34.5% in the control; p = 0.1). Tocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated SARS-CoV-2 patients; it is associated with significantly longer actual ventilator-free periods, and insignificantly lower mortality and higher superinfection.

“Ventilator-free days” composite outcome in patients with SARS-CoV-2 infection treated with tocilizumab: A retrospective competing risk analysis

BackgroundSARS-CoV-2 infection demonstrates a wide range of severity, with more severe cases presenting with a cytokine storm with elevated serum interleukin-6; hence, the interleukin-6 receptor antibody tocilizumab was used for the management of severe cases. ObjectiveTo explore the effect of tocilizumab on ventilator-free day composite outcomes among critically ill patients with SARS-CoV-2 infection. MethodsThis retrospective propensity score-matching study compared mechanically ventilated patients who received tocilizumab to a control group. ResultsTwenty-nine patients in the intervention group were compared to 29 controls. The matched groups were similar. The ventilator-free days composite outcome was higher in the intervention group (sub-distribution hazard ratio 2.7, 95% confidence interval [CI]: 1.2–6.3; p = 0.02), the mortality rate in the intensive care unit was not different (37.9% vs 62%, p = 0.1), and actual ventilator-free days were significantly longer in the tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio for death in the tocilizumab group (HR 0.49, 95% CI: 0.25–0.97; p = 0.04). Positive cultures were not significantly different among the groups (55.2% vs 34.5% in the tocilizumab and control groups, respectively; p = 0.1). ConclusionsTocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated patients with SARS-CoV-2 infection. It is associated with significantly longer actual ventilator-free days, insignificantly lower mortality, and higher superinfection.

Abstract CT565: Clinical and translational results of a phase I study, tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer

Abstract Background: Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC) refractory to gemcitabine + nab-paclitaxel (GN) due to suppression of cancer associated fibroblast (CAF) and increase of drug infiltration in tumor. We sought to determine the safety, recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with GN-refractory MPC. Methods: This phase 1, dose finding trial was conducted following preclinical study of IL-6 signaling blockade in genetically engineered mouse model of pancreatic cancer (pGEMM) and patients-derived CAF, enrolled 10 patients with MPC that had progressed after GN. During the dose-finding part to determine dose-limiting toxicity (DLT), patients initially received TCZ 8 mg/kg on Day 1 and nab-paclitaxel 100 mg/m2 + gemcitabine 750 mg/m2 on Days 2, 9, and 16. The subsequent dose-expansion part used the TCZ dose identified in the dose-finding study. Before Cycle 1 and at the end of Cycle 1, biopsy of liver metastasis was performed 3 to 5 hours after levofloxacin (LVXF) administration to measure LVFX infiltration in tumor using matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). Results: In pGEMM tumor, mouse IL-6 receptor antibody plus GN led pathological response. The growth of CAFs from patients with pancreatic cancer was inhibited by TCZ. In this phase I study, no DLTs occurred and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events (TEAEs) occurred in 80% of patients (Grade ≥3 in 60%) with decreased neutrophil count (n=5, 7 events) being the most common TEAE. Disease control rate was 80·0% (95%CI: 44·4-97·5) and tumor reduction during cycle 1 was observed in 4 patients who were defined as responder. In paired-biopsied samples, decrease of phosphorylated (p) STAT3 expression in tumor was observed in 7 of 8 patients (88%). Responder-related biological activities were increase of cleaved PARP expression of tumor nuclei (P = 0.01), decrease of proliferative CAF (P = 0.08), and increase of LVFX infiltration in tumor (P = 0.04). Decrease of pSTAT3 expression (P = 0.02) was favor to increase of LVFX infiltration against increase of gamma-H2AX, an index of gemcitabine exposure (P = 0.20). Conclusion: TCZ+GN-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and gain of intratumoral drug infiltration in MPC. Citation Format: Shuichi Mitsunaga, Masafumi Ikeda, Kazunori Aoki, Kyoko Yamaguchi, Noriaki Sawada, Etsuko Fujii, Masanobu Nishidate, Takashi Fujitomo, Hideaki Mizuno, Yoko Kayukawa, Atsuhiko Kato, Mayu Makikawa, Hiroshi Imaoka, Mitsuhito Sasaki, Kazuo Watanabe, Hiroyuki Tsunoda, Kimio Terao, Atsushi Ochiai. Clinical and translational results of a phase I study, tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT565.

Treatment of high fat diet-induced obese pregnant mice with IL-6 receptor antibody does not ameliorate placental function and fetal growth restriction.

Pregnancy complications and adverse birth outcomes are in part fueled by the rise in obesity and its associated co-morbidities in western societies. Fetal healthy development and placental function are disturbed by an obese, inflammatory environment associated with cytokines, such as interleukin-6, causing inadequate supply of nutrients to the fetus and perinatal programming with severe health consequences. Mice received high fat diet (HFD) before and during gestation to induce obesity. We performed an IL-6 receptor antibody (MR16-1) treatment in pregnant obese mice at embryonic days E0.5, E7.5 and E14.5 to investigate whether this could ameliorate HFD-induced and obesity-associated placental dysfunction, evaluated by stereology and western blot, and improve offspring outcome at E15.5 in obese dams. We observed fewer fetuses below the 10th percentile and placental vascularization was less aggravated following MR16-1 treatment of obese dams, showing slight improvements in labyrinth zone (Lz) vascularization. However, placental dysfunction and fetal growth restriction were still apparent in MR16-1 dams compared to lean control dams. Molecular analysis showed significantly elevated IL-6 level in placentas of MR16-1 treated dams. Treatment with MR16-1 blocks IL-6 signaling in the placenta, but has only limited effects on preventing HFD-associated placental dysfunction and offspring outcomes in mice, suggesting further mechanisms in the deterioration of placental vascularization and fetal nutrient supply as a consequence of maternal obesity.

Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade.

Interleukin-6 (IL-6) is implicated in skeletal muscle wasting and in regulating skeletal muscle hypertrophy in the healthy state. This work aimed to determine the role of IL-6 in regulating systemic protein and amino acid metabolism during rest, exercise, and recovery in lean and obese humans. In a nonrandomized, single-blind design, 12 lean and 9 obese individuals were infused first with 0.9% saline (Saline), secondly with the IL-6 receptor antibody tocilizumab (Acute IL-6R ab), and 21 days later with saline while still under tocilizumab influence (Chronic IL-6R ab). Outcome measures were determined before, during, and after 90 minutes of exercise at 40% Wattmax by isotope dilution technique, using primed continuous infusion of L-[ring-D5]phenylalanine and L-[D2]tyrosine. Main outcomes measures included systemic protein turnover and plasma amino acid concentrations. We saw no effect of acute or chronic IL-6 receptor blockade on protein turnover. In lean individuals, chronic IL-6 receptor blockade increased plasma concentrations of total amino acids (rest Δ + 186 μmol/L; 95% CI, 40-332; recovery Δ + 201 μmol/L; 95% CI, 55-347) and essential amino acids (rest Δ + 43 μmol/L; 95% CI, 12-76; recovery Δ + 45 μmol/L; 95% CI, 13-77) independently of exercise but had no such effect in obese individuals (total amino acids rest Δ + 63 μmol/L; 95% CI, -170 to 295, recovery Δ - 23 μmol/L, 95% CI, -256 to 210; essential amino acids rest Δ + 26 μmol/L; 95% CI, -21 to 73, recovery Δ + 11 μmol/L; 95% CI, -36 to 58). IL-6 receptor blockade has no effect on protein turnover in fasting lean and obese humans during rest, exercise, and recovery. Chronic IL-6 receptor blockade increases total and essential amino acid concentrations only in lean individuals.

A Novel Humanized Anti-Interleukin-6 Antibody HZ0408b With Anti-Rheumatoid Arthritis Therapeutic Potential.

Interleukin-6 (IL-6), a pleiotropic cytokine that regulates immune responses and inflammatory reactions, plays a pivotal role in the development of rheumatoid arthritis (RA). Blockade of IL-6 signaling with the monoclonal antibody (mAb) represents an important advancement in RA treatment. Although two IL-6 receptor antibodies are already available in the clinic, there is no mAb specifically targeting the human IL-6 to block IL-6 signaling for RA treatment. In this study, we have developed a novel humanized anti-IL-6 mAb HZ-0408b with potent binding and neutralizing activity to human IL-6. We demonstrated that HZ-0408b has a high species specificity and low cross-reactivity. Moreover, HZ-0408b showed a more potent inhibitory effect on IL-6 signaling than Siltuximab, an FDA-approved anti-IL-6 chimeric mAb. HZ-0408b is comparable to Olokizumab, a humanized mAb against IL-6 that is already in phase III studies. We observed that HZ-0408b is well tolerated at doses that can achieve therapeutic serum levels in cynomolgus monkey. Most importantly, we proved that HZ-0408b treatment significantly ameliorated joint swelling after the onset of arthritis and dramatically reduced plasma C-reactive protein (CRP) levels in a monkey collagen-induced arthritis (CIA) model. Collectively, our findings using non-human primates indicate that humanized anti-IL-6 mAb HZ-0408b has excellent safety and efficacy profiles for RA therapy.

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.ResultsPatients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Hope for patients with neuromyelitis optica spectrum disorders - from mechanisms to trials.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.